DESCRIPTION (adapted from the application) My academic and clinical experience of the past fourteen years have laid the foundation for success in studying the pathogenesis of PBC. The combination of a Ph.D. and M.D. allows one to more easily take insights from the bedside to the research bench and back again. Working within a newly established PBC research center at Mount Sinai Medical Center will give me the intellectual and technical support necessary for the transition to an independent investigative career. Initially, I will focus on the role of apoptotic cholangiocytes in the pathogenesis of PBC. Later, I plan to use these findings to develop an animal model of PBC in which potential treatment strategies can be tested. Additionally, I intend to investigate in greater detail the role of protein sulfhydryl oxidation in apoptotic signaling pathways. My clinical and teaching activities will increase over time, but I will remain focused on a translational research career. Our preliminary results suggest that in patients with PBC, apoptotic cholangiocytes are the source of immunogenic PDC-E2, the major PBC autoantigen, that is responsible for the activation of autoreactive B cells. Autoantibodies recognize only the reduced sulfhydryl form of PDC-E2, yet persistence of PDC-E2, in a reduced state occurs only in select cell types, such as cholangiocytes, following apoptosis. Whether or not presentation by antigen presenting cells of novel peptides derived from reduced PDC-E2 in apoptotic cholangiocytes is similarly responsible for the activation of autoreactive T cells is unknown. This issue is important since autoreactive T cells are thought to be pathogenic in PBC and not simple secondary to cholangiocyte damage. To account for this paradox, we have developed a model of PBC pathogenesis in which an initial subclinical episode of biliary inflammation leads to self sustaining biliary inflammation following activation of PDC-E2 specific T cells in susceptible individuals. The crux of this model is whether or not healthy cholangiocytes engulf apoptotic cholangiocytes and present novel peptides derived from this exogenous source of reduced PDC-E2. In this proposal, we aim to determine the following: 1) whether autoreactive T cells from patients with PBC preferentially respond to peptides derived from reduced, rather than oxidized, PDC-E2;2) the antigen presenting cell that most effectively activates autoreactive T cells following incubation with exogenous sources of reduced PDC-E2; and 3) whether PBC patient cholangiocytes engulf apoptotic cells in vivo. Together, these studies will help determine whether autoreactive T cells in patients with PBC are truly pathogenic or simply secondary to idiopathic cholangiocyte destruction.